Greenhouse gas emissions and botulinum neurotoxin packaging

There are currently two botulinum neurotoxin (BoNT) formulations commercially available in Canada. The physical properties of the two products differ, notably with respect to storage temperature requirements. This can impact not only the storage of BoNT products at the hospital pharmacy systems level, but also on the environmental impact of shipping, distribution and waste disposal. The purpose of this study was to compare the greenhouse gas (GHG) emissions of the secondary packaging materials for two commercially available BoNT products, Botox® (onobotulinumtoxinA, manufactured by Allergan Inc) and Xeomin® (incobutulinumtoxinA, manufactured by Merz Pharmaceuticals GmbH & Co KGaA).

Methods: Comparable sample shipments of Botox® and Xeomin® were evaluated. The online COMPASS software system was used to estimate the GHG based on a life-cycle assessment of the secondary packaging of each shipment, measured in units of kilograms of CO2 equivalents (kg-CO2e).

Results: Each sample shipment of BoNT product included eight individually packaged vials. The estimated total GHG emissions from the secondary packaging of the two shipments differed substantially, with the Botox® shipment estimated at 3.5705kg CO2e versus the Xeomin® shipment at 0.0389kg CO2e. The main difference in GHG was accounted for by the cold chain supply management requirements for the Botox® shipment, which included an inner polystyrene container as well as dry ice.

Conclusion: The Botox® shipment was estimated to generate 100-times the GHG emissions of the Xeomin® shipment. The excess secondary packaging required for cold chain supply management imposes not only a greater environmental impact, but also represents a greater burden for hospital pharmacy systems in terms of storage space, refrigerated storage capacity, and disposal.

It is estimated that US hospitals generate approximately 6600 tons of waste per day, and that 80 tons of this is non-hazardous solid waste such as paper, cardboard, metal, glass and plastics.(1) Drug manufacturers are developing innovative strategies to increase the sustainability of their product packaging, such as using lean manufacturing, weight and waste reductions, and more efficient energy-saving packaging lines. Several pharmaceutical manufacturers have joined the Sustainable Packaging Coalition (SPC), an industry working group that is a project of the non-profit institute GreenBlue.(2) Other efforts to reduce greenhouse gas (GHG) emissions are also gaining traction in the pharmaceutical industry. For example, drug distributor McKesson Corp recently announced an initiative aimed at reducing CO2 emissions and drug distribution costs.(3) Using an analytics technology developed by IBM, efficiencies in supply chain, distribution network, supply planning, inventory positioning, vehicle routing and sustainability management have been identified and are now being implemented. The system promises to be particularly valuable for pharmaceuticals that require maintenance of the cold chain, such as vaccines and insulin, by keeping these products in one central refrigeration facility.

Efficiencies in the packaging and transportation of other pharmaceutical products, including botulinum neurotoxin (BoNT) products, could be environmentally beneficial as well. These agents are used therapeutically for the treatment of a variety of neurological and non-neurological conditions, including dystonia, spasticity, blepharospasm, strabismus, and for cosmetic applications such as reduction of facial wrinkles.(4–8) The mechanism of action of BoNT involves binding to cholinergic nerve terminals and reducing the release of acetylcholine, which results in neuromuscular blockade.(8) The effect is temporary, with recovery occurring through sprouting of proximal axons and muscle re-innervation.(9) Eventually, the original neuromuscular junction regenerates, with a persistence of effectiveness lasting up to several months, depending on the clinical condition treated.(5)

There are currently two formulations of BoNT commercially available in Canada: Botox® (onabotulinumtoxinA, manufactured by Allergan Inc); and Xeomin® (incobotulinumtoxinA, manufactured by Merz Pharmaceuticals GmbH & Co KGaA). While the two products contain the same active neurotoxin type A molecule, they are manufactured using distinct processes. The process for manufacturing incobotulinumtoxinA results in an isolated neurotoxin type A with a lower antigen load, whereas that for onabotulinumtoxinA generates both the active neurotoxin as well as accessory proteins.(8,10,11) Head-to-head studies have been conducted in more than one thousand patients to date. The results suggest the two products have similar diffusion properties and clinical efficacy when administered at equivalent doses. In two large comparative equivalent dose studies in subjects with either cervical dystonia(12) or blepharospasm,(13) the use of similar reconstitution, dilution and injection techniques resulted in similar levels of efficacy, safety, tolerability, onset of effect, waning and duration of effect. Another study comparing the two products for the treatment of glabellar frown lines further supports equivalent efficacy and safety.(14) Finally, a non-controlled study for the treatment of a variety of clinical conditions suggests that patients receiving onabotulinumtoxinA can be safely converted to incobotulinumtoxinA using a conversion ratio of 1:1, with no apparent changes in efficacy.(15)

Of particular relevance to hospital pharmacists is the difference in storage requirements between the two products: Xeomin® can be transported and stored at room temperature whereas Botox® requires maintenance of cold chain conditions (that is, between 2 and 8oC) from the time of manufacture until reconstitution and administration (Table 1).(4,8,16,17) Maintenance of the cold chain introduces several challenges, including special transportation and storage, and  potentially higher costs due to product wastage if the cold chain is breached. Furthermore, lack of or diminished therapeutic response may result from inappropriate storage.(16) Notably, differences in packaging requirements for temperature-controlled products could also exert a greater environmental impact. This study was undertaken to compare the environmental ‘foot print’ of the secondary packaging of the two commercially available BoNT products in Canada that are administered with equivalent (1:1) dosing, based on their estimated GHG emissions assessed using life-cycle metrics.

Secondary packaging for sample shipments containing the same number of empty product units (eight glass vials, empty of product) were compared to ensure a like-for-like comparison. Both sample products were delivered via unrefrigerated courier van. Primary packaging (that is, glass vials and individual boxes) was excluded from the analysis; the glass vials and boxes of the two products were similar in size and appearance, and were not expected to provide substantial differences in terms of their GHG emissions. Secondary packaging included an outer corrugated cardboard shipping box (both products); a sheet of Kraft paper (Xeomin® shipment); an inner polystyrene box (Botox® shipment); and dry ice (Botox® shipment). The sample shipments were assumed to be representative of typical shipments to end users. Transportation of the product during each aspect of its production cycle (for example, extraction, manufacturing, warehousing) was not included in the boundaries of this evaluation because the information on modes of transportation, vehicle types, container shipment configuration, and multiple points of final sale were unavailable for one or both products.

A standard Mettler Toledo® PS6L shipping scale was used to weigh each component of the secondary packaging to within 0.01kg. Each component of the secondary packaging was weighed a single time.

Greenhouse gas (GHG) emissions associated with the secondary packaging of the sample shipments of each BoNT product were assessed using the life-cycle assessment software program, COMPASS (developed by the Sustainable Packaging Coalition®, SPC; available online at www.design-compass.org). This is an online software tool that provides a comprehensive environmental profile of packaging alternatives based on life-cycle assessment metrics and design attributes. The life-cycle approach accounts for environmental impacts associated with the materials and processes used to bring packaging to market, and allows decision-makers to incorporate environmental parameters alongside economic factors (Table 2).(18)

COMPASS utilises internationally recognised methodologies and consistent data modelling using relevant and credible data sources. The assessment method and data have been independently verified by member companies within the SPC, and is supported by the US Environmental Protection Agency. The consumption and emission metrics in COMPASS are calculated using industry average life-cycle inventory that represent unit process level data. The US Life-Cycle Inventory (LCI) database, and Ecoinvent, a Swiss LCI database, are the main sources of LCI data used by COMPASS. Due to the lack of applicable US and Canadian data in some instances, European data from Ecoinvent are used as a proxy until equivalent US data become available. All conversion and end-of-life data are derived from Ecoinvent. For non-European data where proxy European data are used, appropriate electricity grid mix replaces European electricity (applied to US and Canadian data sets at the time of this study).(18)

COMPASS does not possess the capabilities to assess the LCI of dry ice. Since no data were available for dry ice as a packaging material, the emission factor used to estimate the associated GHG emissions resulting for the dry ice component of the secondary packaging for Botox® was that of pure carbon dioxide (CO2).

Life-cycle assessment (LCA) was conducted using the COMPASS software to calculate the impacts of eight life-cycle metrics on a per kilogram basis for each material included in the COMPASS analysis.

The breakdown of the constituents of each product sample shipment is listed in Table 3 and described below.

Both BoNT sample shipments were delivered packaged in corrugated cardboard. The corrugated cardboard box containing the Botox® samples had a mass of 407.70g compared with 226.50g for the box containing the Xeomin® samples. The secondary packaging materials for the Xeomin® shipment consisted entirely of fibre-based materials, including a sheet of unbleached Kraft paper with a mass of 45.30g.

It was assumed that the cardboard boxes used to ship each product contained 12% post-consumer recycled (PCR) content, as per the industry standard and the minimum PCR assumed by the COMPASS software tool. The unbleached Kraft paper was modeled assuming no post-industrial or PCR content. All fibre-based materials were also assumed to have been harvested from non-certified sources, meaning that none of the fibre-based materials were from suppliers certified through the Forest Stewardship Council (FSC) or Sustainable Forestry Initiative (SFI).

The shipment for Botox® contained an inner polystyrene box with a mass of 430.35g. The polystyrene box was used as a form of insulation to prolong the life of the dry ice that refrigerates the product and maintains the temperature‑controlled conditions.

To maintain cold chain conditions during shipping of Botox®, a block of dry ice with a mass of 2174.40g (at the time of delivery) was included in the polystyrene box. Dry ice is used to keep perishable products including some pharmaceuticals cool during shipping because it sublimates from solid to gas, offering packaging benefits over ice melt-water.

The COMPASS assessment of the GHG emissions of the secondary packaging of each of the BoNT sample shipments is listed in Table 3. When all components of the secondary packaging are considered, the Botox® sample shipment was estimated to emit 3.5316kg CO2e more than that of an equivalent sample shipment of Xeomin®. Thus, the Botox® shipment emits approximately 100-times the GHG emissions of Xeomin®. The difference is accounted for primarily by the requirement for refrigerant agents for Botox® but not Xeomin®, which accounted for 72% of the total sample shipment mass and 61% of the estimated GHG emissions.

To our knowledge, this is the first study to objectively compare the GHG emissions from the secondary packaging of the two BoNT products that are currently available in Canada. While both these products share similar clinical efficacy and safety, they differ in non-clinical pharmaceutical properties that affect their storage, shelf life and secondary packaging requirements. Indeed, maintenance of cold chain conditions during shipping and delivery by one product, Botox®, accounted for much of the 100-fold higher estimated GHG emissions compared to a similar sample shipment of Xeomin®, a comparable BoNT product that does not require refrigeration.

Life-cycle assessment is being used in other areas of the pharmaceutical industry to evaluate differences in sustainability of packaging of various pharmaceutical products. An end result of such assessments is the innovation of new packaging materials or formats that have a smaller ecological ‘foot print.’ For example, a case study comparing the environmental burden of two different packages that are used to deliver a set of six syringes to hospitals found a more than fourfold difference in CO2 emissions. The more environmentally sustainable packaging was also associated with a cost saving due to volume optimisation and a lesser amount of packaging overall.(19) Our study estimates that the secondary packaging materials of a sample shipment of Botox® emits 100-times more GHG than a comparable sample shipment of Xeomin®. To put these findings into context, if Merz Pharmaceuticals distributed 1000 standard shipments of Xeomin®, the secondary packaging would result in 38.9kg CO2e emissions. In contrast, the distribution of 1000 standard shipments of Botox® would result in 3570.5kg CO2e emissions. Using the RETScreen® International software version 4 (available as a free download from the Natural Resources Canada website at www.retscreen.net/ang/home.php), the difference in GHG emissions between the Xeomin® and Botox® shipments could be equated to removing 646 cars or light trucks from the road for a period of one year (Table 4). These GHG emissions could be offset by the purchase of carbon offsets from a third-party certified carbon offsetting company for a cost of approximately $1.75 CDN (as of June, 2011) for Xeomin®, thereby enabling Merz Pharmaceuticals to offer their clients secondary packaging that is carbon neutral. In contrast, it would cost approximately $160.65 CDN for Allergan to purchase carbon offsets to make the secondary packaging of 1000 standard shipments of Botox® carbon-neutral.

Limitations of this study include the small number of samples evaluated; the inability to estimate adequately GHG emissions due to unknown transportation factors; and the lack of emissions data for dry ice in the COMPASS system, requiring an estimation using a conversion factor of 1:1 (that is, 1g of dry ice releases 1g of CO2 into the atmosphere as it sublimates). Furthermore, measurement of the weight of dry ice at the point of delivery would be expected to be less than at the point of origin due to losses by sublimation over time. This could not be estimated without more detailed information on the time, route and temperature during delivery. Therefore, ours is a conservative analysis that probably underestimates the global contribution of dry ice to the GHG emissions of the Botox® shipment.

In conclusion, our study suggests a 100-fold difference in the carbon foot print of the secondary packaging of two comparable BoNT sample shipments. The excess packaging required for cold chain supply management imposes not only a greater environmental impact, but also represents a greater burden for hospital pharmacy systems in terms of storage space, refrigerated storage capacity and disposal.

1. American Hospital Association. Hospital Environmental Sustainability. Topic: Waste Reduction. Website available at www.hospitalsustainability.org/topic_waste.shtml (accessed 12 October 2011).
2. Sustainable packaging reaches pharmaceuticals and medical devices. Pharmaceutical & Medical Packaging News. Poster Oct 9, 2009. www.pmpnews.com/article/sustainable-packaging-reaches-pharmaceuticals-and-medical- devices (accessed 25 May 2011).
3. Healthcare Packaging. McKesson teams with IBM for sustainable supply chain. Posted Dec 1, 2010. www.healthcarepackaging.com/archives/2010/12/mckesson_teams_with_ibm_for_su.php (accessed 25 May 2011).
4. Dressler D, Benecke R. Pharmacology of therapeutic botulinum toxin preparations. Disabil Rehabil 2007;29:1761–8.
5. Lebeda FJ et al. Temporal characteristics of botulinum neurotoxin therapy. Expert Rev Neurother 2010;10:93–103.
6. Kostrzewa RM, Segura-Aquilar J. Botulinum neurotoxin: evolution from poison, to research tool—onto medicinal therapeutic and future pharmaceutical panacea. Neurotox Res 2007;12:275–90.
7. Apostolidis A, Fowler CJ. The use of botulinum neurotoxin type A (BoNTA) in urology. J Neural Transm 2008;115:593–605.
8. Park J, Lee MS, Harrison AR. Profile of Xeomin® (incobotulinumtoxinA) for the treatment of blepharospasm. Clin Ophthalmol 2011;5:725–32.
9. de Paiva A et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parents terminals. Proc Natl Acad Sci USA 1999;96:3200–5.
10. Gollomp S. Neurotoxin therapy: a closer look at the four options. Pract Neurol 2011;March/April:27–33.
11. Macarthur D. Storage and other variability between botulinum toxin brands. Hospital Pharmacy Europe 2010;51:49–51.
12. Benecke R et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005;64:1949-51.
13. Roggenkamper P et al. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 2006;113:303–12.
14. Sattler G et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines. Dermatol Surg 2010;36(Suppl 4):2146–54.
15. Dressler D. Routine use of Xeomin in patients previously treated with Botox: long term results. Eur J Neurol 2009;16(Suppl 2):2–5.
16. Allergan Inc. Botox® (botulinum toxin type A for injection Ph. Eur.) Product Monograph. Date of approval: 21 December 2011.
17. Merz Pharmaceuticals GmbH. Xeomin® (Clostridium Botulinum Neurotoxin Type A (150 kD), free from complexing proteins) Product Monograph. Date of approval: 16 February 2011.
18. Sustainable Packaging Coalition. COMPASS: Comparative Packaging Assessment. www.design-compass.org. 2008.
19. Zurkirch M. How to measure sustainability of pharmaceutical packaging. Next Generation Pharmaceutical. Posted Jan 27, 2011. www.ngpharma.eu.com/article/How-to- measure-sustainability-of-pharmaceutical-packaging/ (accessed 25 May 2011).